Acquired Immune Deficiency Syndrome, or AIDS, causes an immunosuppresslon of certain cells critical to eliciting an immune response. AIDS is caused by the Human Immunodeficiency Virus or HIV.
AIDS is characterized by progressive debilitation of the host immune system, chronic wasting disease, chronic diarrhea, dementia, and increased incidence of unusual cancers. A consequence of decreasing immune system function is the onset of life threatening opportunistic infections due to pathogens such as Pneumocystis carinii and Mycobacterium avium complex that are rarely serious for immunocompetent individuals. Wasting disease and chronic diarrhea are the principal enteropathic sequelae of HIV-1 infection. Dementia is believed a consequence of HIV-1 infection in the central nervous system. The unusual cancers include lymphoma of the brain and Kaposi's sarcoma that develops in almost one third of AIDS patients. The principal laboratory sign of progressive HIV-1 infection is the loss of CD4+T lymphocytes and this change is linked to the profound dysregulation of immune responses and the general immunodeficiency in the cell mediated branch of the immune system.
HIV is a retrovirus or RNA virus which has the ability to copy its RNA into new double stranded DNA that can be integrated into the DNA of an infected cell. This conversion from RNA to DNA is catalyzed by an RNA directed DNA polymerase or reverse transcriptase (RT). Retroviruses exist in a multitude of forms involving varying degrees of infectivity and pathogenicity. Endogenous retroviruses are distinguished from exogenous retroviruses in that they are usually carried benignly in the germ line. Most of these endogenous retroviruses are defective. Exogenous retroviruses are more pathogenic and fall in four major groups: (1) Murine Leukemia virus group; (2) the mouse mammary tumor virus/Rous Sarcoma virus group; (3) the human T Cell leukemia virus (HTLV) group; and (4) the lentivirus group. HIV falls into the last category.
Specifically, three outbreaks of primate lentiviruses have been recognized: HIV-1 in central Africa, Asia, North America and Europe; HIV-2 in West Africa; Simian Immunodeficiency Virus (SIV) in captive and wild nonhuman primate populations. Comparative analysis between HIV-1 and HIV-2 nucleotide sequences show little homology, only 42%. Conversely, HIV-2 is closely related to SIV.
HIV infection in humans and SIV infection in monkeys is primarily a disease involving viral replication within the individual lymph nodes and other solid tissues of the secondary immune system. An early consequence of infection is the onset of lymphadenopathy indicating the substantial involvement of tissues in the secondary lymphoid system (the solid tissue sites including linings of the mucosal surfaces, lymph nodes, spleen, thymus, and others). The period of clinical latency disguises an underlying virological activity as HIV-1 infection disseminates throughout the secondary lymphoid system and causes the progressive destruction of immune capacity.
The lymph node is a microcosm of HIV and SIV infection that highlights the competition between virus destruction and virus replication because both of these processes require T lymphocyte activation. T lymphocytes are included in the category of white blood cells and are produced in spleen, thymus, and bone marrow. They are essential elements in all immune reactions by virtue of their key regulatory functions. Another population of immune cells are termed macrophages; they are also involved in several immune functions and are considered essential. Specific subpopulations of T lymphocytes and macrophages present the CD4 molecule on their cell surface. This molecule binds HIV-1 to these cells and facilitates their destruction. The level of circulating T lymphocytes in AIDS patients is depressed and this is especially evident for the T helper cell subset. Whereas the ratio of T.sub.H to T.sub.S (T suppressor cells) cells in normal humans averages 2.3, the T.sub.H /T.sub.S ratio in AIDS patients is less than 0.9.
Research on therapy for HIV-1 infection principally utilizes conventional approaches that identify specific biochemical features of this virus and develop small molecule drugs to block the cycle of virus replication. These methods have been largely unsuccessful because of the highly variable nature of this virus, leading to rapid evolution of drug resistant variants, the highly regulated nature of the virus life cycle, allowing extended periods of decreased virological activity without loss of viral genomic sequences, and the intimate relationship between factors that promote virus replication and those factors that promote immune responses to the virus.
Vaccine efforts have not been successful and practical difficulties in animal model development and human clinical testing combine to slow progress in this area.
Not only have vaccines failed in combating AIDS, but various drugs also do not rid the body of the virus. For example, Azidothymidine, or AZT, is a thymidine analogue which inhibits in vitro replication of HIV. Unfortunately, this drug does not work as well in an in vivo environment and has serious side effects.
Current efforts in therapy development include a variety of strategies for increasing immune system activity and/or decreasing CD4 cell killing. Therapeutic vaccination and adoptive transfer of CD8+T-lymphocyte clones are intended to increase effectiveness of immune responses to virus. Genetic modification of CD4+T-lymphocytes including transdominant modifications of HIV proteins, RNA decoys, antisense RNA, ribozymes and modifications of cellular proteins (intracellular antibodies, soluble CD4) are all intended to increase cellular resistance to virus killing mechanisms. Several of these strategies are now entering clinical trials.
However, significant conceptual and technical hurdles must be overcome before the promise of gene therapy or vaccines for HIV infection can be realized.
It is clear from the difficulty in treating HIV infection that it has a complex and varied disease course. Therefore, it is necessary to evaluate the relationship between route of infection, virus strain, and likely pattern of disease progression as important steps toward understanding the factors controlling epidemic HIV spread and the resulting diseases. Imprecise information about the route and timing of initial infection, the possibility that reinfection can occur, and the complex virus populations present within infected individuals are important confounding factors that inhibit understanding the host pathogen's interactions involved in epidemic infection.